EP0029247A1 - Acides alcényl-thiényl-alcane carboxyliques et leurs dérivés, procédé pour leur préparation et médicaments les contenant - Google Patents

Acides alcényl-thiényl-alcane carboxyliques et leurs dérivés, procédé pour leur préparation et médicaments les contenant Download PDF

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Publication number
EP0029247A1
EP0029247A1 EP80107163A EP80107163A EP0029247A1 EP 0029247 A1 EP0029247 A1 EP 0029247A1 EP 80107163 A EP80107163 A EP 80107163A EP 80107163 A EP80107163 A EP 80107163A EP 0029247 A1 EP0029247 A1 EP 0029247A1
Authority
EP
European Patent Office
Prior art keywords
thien
oct
enyl
oxo
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP80107163A
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German (de)
English (en)
Other versions
EP0029247B1 (fr
Inventor
Hans-Heiner Dr. Lautenschläger
Hans Dr. Betzing
Johannes Dr. Winkelmann
Manfred Dr. Probst
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
A Natterman und Cie GmbH
Original Assignee
A Natterman und Cie GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by A Natterman und Cie GmbH filed Critical A Natterman und Cie GmbH
Priority to AT80107163T priority Critical patent/ATE3039T1/de
Publication of EP0029247A1 publication Critical patent/EP0029247A1/fr
Application granted granted Critical
Publication of EP0029247B1 publication Critical patent/EP0029247B1/fr
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Alkali ion or a straight-chain or branched saturated hydrocarbon group with 1-6 carbon atoms means to have anti-inflammatory properties without having an irritant effect on the gastric mucosa.
  • alkenyl-thienyl-alkane carboxylic acid and its derivatives can be prepared by several process methods known per se to the person skilled in the art.
  • a process according to the invention for the preparation of the compounds of the general formula (I) with the keto group in the alkenyl radical, in which R 1 and R 2 together represent an oxygen atom consists in that aldehydes of the general formula where n and R 3 have the meanings given for formula I in an organic solvent suitable for Wittig-Horner reactions, such as, for example, glycol dimethyl ether, with a 2-oxoheptylphosphonic acid dialkyl ester, for example the 2-oxoheptylphosphonic acid dimethyl ester, with the aid of a half-base which is customary for such reactions, such as eg reacting sodium hydride.
  • the salts can also be obtained by reacting the corresponding acids of the general formula (I), in which R 3 is a hydrogen atom, with alkali metal hydroxides or alkali metal carbonates in aqueous or alcoholic aqueous solution, whereupon the salts are obtained by subsequent concentration of the solutions. By reacting calcium carbonate or ammonia, the calcium or. Ammonium salt.
  • the invention further relates to a process for the preparation of the compounds of the general formula (I), in which R is a hydrogen atom and R 2 is a hydroxyl group, in which, starting from the corresponding keto compounds, in a suitable medium, such as, for example, an alcoholic-aqueous solvent system with a reducing agent , such as sodium borohydride, the keto group is reduced.
  • the new thiophene derivatives of the formula (I) show valuable pharmacological properties, such as antiphlogistic and antiarteriosclerotic activity, in very low doses. They also show antiulcerogenic properties and thus excellent stomach tolerance and low toxicity. They can therefore be used in particular for the treatment of inflammatory and arteriosclerotic diseases with, at the same time, favorable gastrointestinal properties.
  • the new compounds of formula (I) can e.g. administered orally, by injection or rectally in suitable formulations, which are solid or liquid in the form of suspensions or solutions.
  • suitable formulations are tablets, powders, capsules, granules, troches, ampoules, syrups and suppositories. Lactose, starch, etc. are suitable as carriers.
  • the preparation of the compounds according to the invention is explained in more detail by the following examples.
  • the aldehydes of the general formula II used as starting substances were synthesized by methods known from the literature [Vilsmeyer synthesis, e.g .: B.P. Fabrichnyi et al., Zhur. Obshchei Khim, 28, 2520-30 (1958) 1 from the corresponding ⁇ - (2-thienyl) alkanoic acid esters.
  • the stated melting points were measured with a Büchi 510 melting point determination apparatus and are not corrected.
  • the IR spectra were recorded with a Perkin-Elmer 257 device.
  • esters of the other alcohols are prepared, for example: 7- [5- (3-oxo-oct-1-enyl) -thien-2-yl] -onanthate , oil, IR (film): 1740, 16 70 , 1 600 cm -1 2- [5- (3-oxo-oct-1-enyl) thien-2-yl] -acetic acid hexyl ester, oil, IR (film) : 1740, 1670, 1605 cm -1
  • aqueous solution is adjusted to pH 5.5-6 with dilute HCl, extracted with ether, the ethereal phase washed with water, dried over Na 2 SO 4 and i.Vac. constricted.
  • the residue is purified by column chromatography (silica gel // benzene / ethyl acetate). Yield: 1.2 g (45%) with mp. 51 ° C.
  • aqueous solution is adjusted to pH 5.5-6 with dilute HCl, extracted with ether, the ethereal phase washed with water, dried over Na 2 S0 4 and i. Vac. constricted.
  • the residue is purified by column chromatography (silica gel // toluene / ethyl acetate). Yield: 6.5 g (74%) with mp 69-70 ° C, IR (in KBr): 1725, 1620 cm -1
  • tablets are pressed, which are then coated in a conventional manner with a coating consisting of sugar, corn starch, talc and tragacanth.
  • Example 5 i.e. the 9- [5- (3-oxo-octyl) -thien-2-yl] -pelargonic acid methyl ester was investigated in a series of comparative pharmacological tests using known standard test methods against indemacine as a known comparative active ingredient.
  • the dosage is generally 50 mg to 5 g, which is applied once or several times a day. Preferably 100 to 500 mg are administered two or three times a day.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
EP80107163A 1979-11-20 1980-11-18 Acides alcényl-thiényl-alcane carboxyliques et leurs dérivés, procédé pour leur préparation et médicaments les contenant Expired EP0029247B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT80107163T ATE3039T1 (de) 1979-11-20 1980-11-18 Alkenyl-thienyl-alkancarbonsaeuren und ihre derivate, verfahren zu deren herstellung und diese enthaltende arzneimittel.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19792946810 DE2946810A1 (de) 1979-11-20 1979-11-20 Alkenyl-thienyl-alkancarbonsaeure und ihre derivate, verfahren zu deren herstellung und diese enthaltende arzneimittel
DE2946810 1979-11-20

Publications (2)

Publication Number Publication Date
EP0029247A1 true EP0029247A1 (fr) 1981-05-27
EP0029247B1 EP0029247B1 (fr) 1983-04-13

Family

ID=6086475

Family Applications (1)

Application Number Title Priority Date Filing Date
EP80107163A Expired EP0029247B1 (fr) 1979-11-20 1980-11-18 Acides alcényl-thiényl-alcane carboxyliques et leurs dérivés, procédé pour leur préparation et médicaments les contenant

Country Status (7)

Country Link
US (1) US4309407A (fr)
EP (1) EP0029247B1 (fr)
JP (1) JPS5686181A (fr)
AT (1) ATE3039T1 (fr)
AU (1) AU6379380A (fr)
DE (1) DE2946810A1 (fr)
ZA (1) ZA807176B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155524A1 (fr) * 1984-03-01 1985-09-25 A. Nattermann & Cie. GmbH Composé omega-aryl-alkylthianyliques, leur procédé de préparation et produits pharmaceutiques les contenant
EP0161904A2 (fr) * 1984-05-10 1985-11-21 E.R. Squibb & Sons, Inc. Ethers tétrahydrofuranyliques et tétrahydrothiényliques substitués
FR2574794A1 (fr) * 1984-12-17 1986-06-20 Squibb & Sons Inc Analogues de prostaglandines tetrahydrothienyl-substitues a action cardiovasculaire
WO1988005045A1 (fr) * 1986-12-29 1988-07-14 The Upjohn Company Analogues du leukotriene b4
EP0319900A2 (fr) * 1987-12-08 1989-06-14 G.D. Searle & Co. B4 Analogues du leucotriène comprenant des groupes furyle, phénylène et thiényle

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4480140A (en) * 1983-03-16 1984-10-30 Koppers Company, Inc. Process for alkylating phenolic compounds to produce ortho or para-monoalkylated or 2,4- or 2,6-dialkylated phenols
US4791133A (en) * 1987-06-26 1988-12-13 G. D. Searle & Co. Phenylene, furyl, and thienyl leukotriene B4 analogues
US6495719B2 (en) * 2001-03-27 2002-12-17 Circagen Pharmaceutical Histone deacetylase inhibitors
US8026280B2 (en) 2001-03-27 2011-09-27 Errant Gene Therapeutics, Llc Histone deacetylase inhibitors
US7842727B2 (en) * 2001-03-27 2010-11-30 Errant Gene Therapeutics, Llc Histone deacetylase inhibitors
US7312247B2 (en) 2001-03-27 2007-12-25 Errant Gene Therapeutics, Llc Histone deacetylase inhibitors
CA2486303C (fr) * 2002-05-22 2013-04-30 Errant Gene Therapeutics, Llc Inhibiteurs d'histone desacetylase bases sur des composes alpha-ceto-epoxydes
AU2003291097A1 (en) * 2002-11-20 2004-06-15 Errant Gene Therapeutics, Llc Treatment of lung cells with histone deacetylase inhibitors
WO2006052916A2 (fr) * 2004-11-08 2006-05-18 Errant Gene Therapeutics, Inc. Inhibiteurs d'histone deacetylase

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2422498A1 (de) * 1973-05-18 1974-12-05 Ciba Geigy Ag Neue thiaprostaglandine und verfahren zu ihrer herstellung
DE2521517A1 (de) * 1974-05-14 1975-11-27 Gyogyszerkutato Intezet Thiazolderivate sowie solche enthaltende arzneimittel und verfahren zur herstellung derselben

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3691202A (en) * 1968-10-25 1972-09-12 Ici Ltd Phenyl-thienyl- and phenyl-furyl malonic acid derivatives
US3781429A (en) * 1972-09-29 1973-12-25 American Cyanamid Co Method of inhibiting ulcerogenesis induced by non-steroidal anti-inflammatory agents
US3937801A (en) * 1973-07-10 1976-02-10 American Home Products Corporation Reducing the incidence of gastrointestinal side effects during the treatment of inflammatory conditions with antiinflammatory drugs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2422498A1 (de) * 1973-05-18 1974-12-05 Ciba Geigy Ag Neue thiaprostaglandine und verfahren zu ihrer herstellung
DE2521517A1 (de) * 1974-05-14 1975-11-27 Gyogyszerkutato Intezet Thiazolderivate sowie solche enthaltende arzneimittel und verfahren zur herstellung derselben

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Band 87, Nr. 21, 21. November 1977 Columbus, Ohio, USA W.J. VLOON et al. "The synthesis of 2-substituted 3-ketotetrahydrothiophenes using a highly active Dieckmann catalyst. 11-Desoxy-9-thiaprostaglandin". Seite 535, Spalte 1, Abstract Nr. 167577b * Formel IV * & Heterocycles, Band 6, Nr. 8, 1977 Seiten 1097 bis 1100 (Eng). *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155524A1 (fr) * 1984-03-01 1985-09-25 A. Nattermann & Cie. GmbH Composé omega-aryl-alkylthianyliques, leur procédé de préparation et produits pharmaceutiques les contenant
EP0161904A2 (fr) * 1984-05-10 1985-11-21 E.R. Squibb & Sons, Inc. Ethers tétrahydrofuranyliques et tétrahydrothiényliques substitués
EP0161904A3 (en) * 1984-05-10 1986-10-15 E.R. Squibb & Sons, Inc. Tetrahydrofuranyl and tetrahydrothienyl substituted ethers
FR2574794A1 (fr) * 1984-12-17 1986-06-20 Squibb & Sons Inc Analogues de prostaglandines tetrahydrothienyl-substitues a action cardiovasculaire
WO1988005045A1 (fr) * 1986-12-29 1988-07-14 The Upjohn Company Analogues du leukotriene b4
US5116981A (en) * 1986-12-29 1992-05-26 The Upjohn Company Antiinflammatory leukotriene B4 analogs
EP0319900A2 (fr) * 1987-12-08 1989-06-14 G.D. Searle & Co. B4 Analogues du leucotriène comprenant des groupes furyle, phénylène et thiényle
EP0319900A3 (en) * 1987-12-08 1990-12-19 G.D. Searle & Co. Furyl, phenylene and thienyl leukotriene b4 analogues

Also Published As

Publication number Publication date
ATE3039T1 (de) 1983-04-15
US4309407A (en) 1982-01-05
DE2946810A1 (de) 1981-05-27
EP0029247B1 (fr) 1983-04-13
AU6379380A (en) 1981-05-28
ZA807176B (en) 1981-12-30
JPS5686181A (en) 1981-07-13

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